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What is a Gene?
Genetic information is key
Top 5 Reasons to Know Your
Family History
5. Family recipes should be kept secret —
family medical history should not.
4. Knowing your risk might save your life.
3. It’s free and you don’t have to leave home.
2. It’s a priceless gift to leave to your
children.
1. Because every family has a story, but not
every family has YOUR story.
https://www.yahoo.com/health/10-reasons-you-should-dig-into-your-family-medical-118232923367.html
Frequency of cell division
 Frequency of cell division varies with
cell type

skin cells
 divide frequently throughout life

liver cells & muscle, bone
 retain ability to divide, but keep it in reserve

mature nerve cells do not divide at all
after maturity
Most Common Screening Tests
 Mammography
 Clinical breast exam
 Breast self-exam
Cell Cycle Control
 Two irreversible points in cell cycle
replication of genetic material
 separation of sister chromatids

 Cell can be put on hold at specific
checkpoints
sister chromatids
There’s no
turning back,
now!
centromere
single-stranded
chromosomes
double-stranded
chromosomes
BRCA genetic testing
• BRCA genetic testing is available to anyone in
Australia through private laboratories. BRCA
gene testing costs differ between laboratories
and start from approximately $900. Although
genetic testing is accessible and becoming
increasingly cheaper it is not always helpful in
clarifying the risk of breast and ovarian cancer
for many people.
Familial Breast Cancer
• Cause 5-10% of all cancer and 25% in women <30 y/o
• BRCA2
•
•
•
•
Causes 40% of familial breast CA
50-70% - breast
15-45% - ovarian
Increased risk for prostate, colon
• BRCA1
• 50-70% - breast
• 20-30% - ovarian
• Increased risk for prostate, pancreatic, laryngeal,
BRCA genetic testing
 BRCA genetic testing is available to
anyone in Australia through private
laboratories. BRCA gene testing costs
differ between laboratories and start from
approximately $900. Although genetic
testing is accessible and becoming
increasingly cheaper it is not always
helpful in clarifying the risk of breast and
ovarian cancer for many people.
Why can’t everyone have free
BRCA genetic testing?
Although, gene testing can be helpful it
does not always provide all the
answers needed to help clarifying a
woman’s level of breast or ovarian
cancer risk. Only 5% of women who
develop breast cancer have a high risk
breast cancer gene involved and of
women with breast cancer who also
have a familial breast cancer cluster
84% of those women do not have a
Why can’t everyone have free BRCA
genetic testing?
Although, gene testing can be helpful it does
not always provide all the answers needed to
help clarifying a woman’s level of breast or
ovarian cancer risk. Only 5% of women who
develop breast cancer have a high risk breast
cancer gene involved and of women with
breast cancer who also have a familial breast
cancer cluster 84% of those women do not
have a BRCA gene mutation.
Common Risk Factors
• Age
• Family history
• Ethnicity
• Lifestyle
• Diet
• Alcohol
• Smoking
Family
History
Chance
Lifestyle
Personal
Cancer
Risk
Aging
Genetics
Environment
Isn’t it just a blood test?
• Positive results
with limited
information
• Inconclusive
results
• Results that don’t
“fit”
• Worry/anxiety
Hereditary breast and ovarian cancer
syndrome caused by mutations in
BRCA1 and BRCA2 genes
• Autosomal dominant cancer predisposition
syndrome
• Associated with high risk for breast and
ovarian cancers and a moderate risk for other
cancers
• Not all individuals who inherit a mutation in
BRCA1 or BRCA2 will develop cancer
(reduced penetrance) and the signs,
symptoms, cancer type, and age of onset of
cancer will vary within families (variable
Breast CA
Ovarian CA
Ov Ca
Died 48
Ov Ca
Dx 40
BRCA1 pos
BRCA1 pos
BRCA1 pos
Prostate CA
BRCA1 neg
33
Prostate Ca
Dx 43
BRCA1 pos Bilateral Br Ca
Dx 30, 2nd Dx 35
Jenny
BRCA1 pos
Jenny has a 50% chance to
inherit the familial BRCA1
gene mutation from her
father
Who should be offered genetic
testing/consultation?
Breast cancer diagnosis at a young age (<35-45 years) [both
invasive and ductal carcinoma in situ]
Ovarian cancer at any age [epithelial]
Male breast cancer
Multiple primaries in the same individual
• e.g. bilateral breast cancer (particularly if the diagnosis was before age
50), breast and ovarian cancer
Breast cancer diagnosis AND a family history of 2+ additional
HBOC- related cancers, including breast, ovarian, prostate
(Gleason ≥7) and pancreatic cancer
High risk ethnicity (Ashkenazi Jewish, Icelandic) and a personal
and/or family history of HBOC-related cancer
Triple negative breast cancer diagnosed <age 60
OR
Probability of 10% or higher to carry a BRCA mutation
Genetics of hereditary
breast and ovarian cancer
syndrome
• BRCA1 (chrom 17) and BRCA2 (chrom 13) are tumor
suppressors
• Mutation leads to inability to regulate cell death and
uncontrolled growth
• >2600 mutations
• Carrier frequency of BRCA1 & BRCA2 mutations
– 1/300 to 1/500 in general population
– 1/40 - 1/50 in Ashkenazi Jewish population
• 3 common mutations in Ashkenazi Jews
DAD
MOM
Consequences of having a BRCA
mutation
Cancer type
Cumulative lifetime
invasive breast cancer
risk in women (by age
70)
Cumulative lifetime
ovarian cancer risk (by
age 70)
Cumulative lifetime
breast cancer risk in
men (by age 70)
Lifetime prostate
cancer risk (by age 70)
Carroll CMAJ 2012
Cancer risk in a mutation carriers of:
General
Population
BRCA1
BRCA2
57%
49%
~12%
40%
18%
~1.3%
6-7%
0.1%
2-6x increased risk
~14%
Increased
(controversial)
n/a
•
Screening and
Surveillance for BRCA
Increased surveillance
gene mutation carriers
– MRI + mammography from age 25-30
• Chemoprevention
– Selective estrogen receptor modulators (SERMs) i.e.
Tamoxifen/Raloxifene ~50% reduction in RR of breast cancer;
reduce BrCA risk in healthy BRCA2 carriers by ~60%
– Aromatase inhibitors (exemestane, anastrozole, letrozole) under
investigation
• Risk-reduction surgery
– Bilateral mastectomy: ~ 90% risk reduction in Br Ca
– Bilateral salpingo-oophorectomy (BSO): 80% reduction in risk of
ovarian/fallopian tube cancer; 50% reduction in risk of BrCA;
Optimal age of BSO=pre-menopause
What do the genetic test results
mean?
Positive test result: Gene mutation known to be
pathogenic found
• The patient has an increased lifetime risk
to develop certain cancers
• Screening and surveillance
recommendations to improve outcome
• Family members are at risk of carrying the
same mutation and of having similar
cancer risks
Treatment options for affected
BRCA mutation carriers
• More frequent, or intensive cancer screening
• Risk-reducing medications
– e.g. tamoxifen or raloxifene
• Risk-reducing surgery
– e.g. mastectomy or bilateral salpingooophorectomy(BS0)
• New adjuvant, neoadjuvant, and metastatic
treatments
– e.g. PARP inhibitors
Moyer Ann Intern Med 2014, Livraghi and Garber BMC Medicine 2015
Screening and Surveillance for BRCA
gene mutation carriers
• Lifestyle modification
– Maintain healthy lifestyle with proper diet, healthy BMI, regular
exercise and limited alcohol consumption
– Stay up-to-date on current screening recommendations
• Prostate CA
– Consider screening beginning at age 40 (e.g. annual digital rectal
examination +/- PSA)
– A number of retrospective studies consistently report that BRCA2
carriers present at a younger age with aggressive disease, higher
rates of lymph node involvement, distant metastasis at diagnosis, and
a higher mortality rate compared with non-carriers
– BRCA1 cancer risk is thought to also be increased, although
controversial
What do the genetic test results mean?
Variant of uncertain significance (VUS): a gene change that
has not yet been categorized as benign or as pathogenic
• The diagnosis of hereditary breast and ovarian
cancer syndrome is neither confirmed nor ruled out
• Some variants may be interpreted as ‘likely
pathogenic’, generally meaning greater than 90%
certainty of being disease causing
– Screening and management may be modified
– Other family members may be offered genetic testing to
try to track the familial gene change and to see if it is
associated with cancer
What do the genetic test results mean?
Variant of uncertain significance (VUS): a gene change that
has not yet been categorized as benign or as pathogenic
• Variants are periodically re-classified and patients are
often encouraged to recontact their genetics clinic
• Other hereditary cancer syndromes may be
considered
• Screening recommendations will be based on a
combination of factors, such as family history and
information about the VUS
Risks/Benefits/Limitations of Genetic Testing
Positive test result: Gene mutation known to be
pathogenic found
Potential Benefits:
• Clinical intervention
may improve outcome
• Family members at risk
can be identified
Potential Risks:
• Adverse psychological
reaction
• Family issues/distress
• Uncertainty -incomplete
penetrance
• Insurance/job
discrimination
• Confidentiality issues
Risks/Benefits/Limitations of Genetic Testing
Negative test result: Familial mutation not found
(true negative)
Potential Benefits:
• Emotional - relief
• Children can be
reassured
• Avoidance of
unnecessary clinical
interventions
Potential Risks:
• Adverse psychological
reaction (i.e. survivor
guilt)
• Complacent attitude to
health
Case 1: Judy
Multiple affected
relatives
Closely related
More than 1
generation affected
Early age of onset
Clustering of related
cancers
What do the genetic test results mean?
Negative test result: affected patient no mutation
identified and there is no known familial mutation
• This result is uninformative
• The diagnosis of hereditary breast and ovarian
cancer syndrome is neither confirmed nor
ruled out
Autosomal dominant inheritance
mother
child
father
child
Each child has 50:50 chance of inheriting the altered gene.
Sporadic cancer
2 normal genes
1 normal gene
1 mutated gene
hormones
viruses chemicals
radiation
2 mutated genes
cancer
Spontaneous mutations
Inherited cancer
1 normal gene
1 mutated gene
hormones
viruses chemicals
radiation
2 mutated genes
Spontaneous mutations
cancer
Searching for the faulty gene
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Genetic Testing
• Technically difficult
• Can only be offered to high risk families
• Can only search small number of high risk
dominant genes
• Can take more than a year to search for the
mutation in a family
• Often cannot locate the mutation for a family
(?unknown genes)
Genetic Testing
• First test in family always done on person who
has had the cancer (mutation search test)
• If no living affected relatives available – cannot
offer genetic test for family
• If a mutation is found predictive testing can be
offered to at-risk relatives:
– If relative doesn’t carry familial mutation they are not
at increased risk of cancer (still at population risk)
– If a person does carry the familial mutation they are at
increased risk of developing cancer
Recent NICE Guidelines on Familial
Breast Cancer
• Women at or near population risk are
cared for in primary care.
• Women at moderate risk are cared for
in secondary care.
• Women at high risk are cared for in
tertiary care.
High Risk
Cancer risks associated with
BRCA1 and BRCA2
Breast and ovarian cancer
Other cancers
• Breast cancer risk ~80%
• Ovarian cancer risk ~45%
• Increased risk of second
primary for women who
have already had breast
cancer
•
•
•
•
Prostate cancer
Male breast cancer
Pancreatic cancer
Colorectal cancer
• Stomach cancer